3-(2-dimethylaminomethylcy clohexyl)phenol retard formulation

ABSTRACT

The invention relates to a dosage form for controlled release of the active ingredient 3-(2-dimethylaminomethylcyclohexyl)phenol, preferably (1R,2R)-3-(2-dimethylamino-methylcyclohexyl)phenol, or one of the pharmaceutically acceptable salts thereof, which
         (i) in vivo achieves the peak plasma level of the active ingredient after 2 to 10 h,   and/or   (ii) in vitro, measured in accordance with the European Pharmacopoeia with a paddle stirrer apparatus in buffer at a pH value of 6.8 (preferably 900 ml), a temperature of 37° C. and 75 rpm releases
           after 0.5 hours 3.0 to 37 wt. %,   after 1 hour 5.0 to 56 wt. %,   after 2 hours 10 to 77 wt. %,   after 3 hours 15 to 88 wt. %,   after 6 hours at least 30 wt. %,   after 12 hours at least 50 wt. %,   after 18 hours at least 70 wt. % and   after 24 hours at least 80 wt. %   
           of the active ingredient originally contained in the dosage form.

The invention relates to a pharmaceutical dosage form with controlledrelease of 3-(2-dimethylaminomethylcyclohexyl)phenol, preferably of the(1R,2R) stereoisomer, or one of the pharmaceutically acceptable saltsthereof.

3-(2-Dimethylaminomethylcyclohexyl)phenol is known from the prior art.It is an orally administrable, analgesically active pharmaceuticalsubstance (cf. for example DE-A 195 25 137, WO 02/43712 and WO02/67916).

Due to the two chiral centres, 3-(2-dimethylaminomethylcyclohexyl)phenoloccurs in the form of four stereoisomers (two enantiomeric pairs),namely as (1R,2R)-, (1S,2S)-, (1R,2S)- and(1S,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol. These fourstereoisomers are of the following structure:

Conventional dosage forms for oral administration of3-(2-dimethylaminomethylcyclohexyl)phenol lead to rapid release of theentire active ingredient dose in the gastrointestinal tract, resultingin rapid onset of the analgesic action. Consequently, treating severechronic pain with 3-(2-dimethylaminomethylcyclohexyl)phenol has hithertomeant administering the medicament at relatively short time intervals,for example four to six times daily, in order to achieve an adequateactive ingredient concentration in the patient's plasma over a 24 hperiod.

However, the necessity of administering frequent doses often results inerrors in taking and in undesirable fluctuations in plasmaconcentration, which have a negative impact on compliance andtherapeutic benefit, in particular in the treatment of chronic pain. Itis furthermore known that, with conventional dosage forms, oraladministration of 3-(2-dimethylaminomethylcyclohexyl)phenol may resultin side-effects, in particular nausea and vomiting.

It is known to provide dosage forms with controlled-release of theactive ingredients contained therein in order to ensure continuousrelease of the active ingredient over an extended period.

Controlled-release formulations for a large number of active ingredientsare known in the prior art. Controlled release is conventionallyachieved by suitable coatings and/or by embedding the active ingredientin a matrix which controls release.

In the case of coated controlled-release formulations, an activeingredient-containing core is provided with a coating of hydrophilicand/or hydrophobic polymers which delays release of the activeingredient. In the case of matrix controlled-release formulations, theactive ingredient is embedded in a polymer matrix which controls releaseof the active ingredient.

However, if a specific release profile is to be achieved for an activeingredient, it is not straightforwardly possible, starting from a knownprior art composition having the desired release profile, simply to swapthe active ingredient contained therein. Instead, the individualphysical and chemical properties of the particular active ingredientmust be taken into account for each individual case. Numerous individualproperties of an active ingredient may accordingly have a considerableinfluence on its release profile. The specific release behaviour of anactive ingredient may be determined, for example, by the dose to beadministered, particle size, particle shape, hardness, hygroscopicity,solubility, dependency of solubility on pH value,hydrophilicity/lipophilicity, acidity/basicity, etc.

The object of the present invention is to provide a pharmaceuticalformulation of 3-(2-dimethylaminomethylcyclohexyl)phenol, preferably the(1R,2R) stereoisomer thereof or one of the pharmaceutically acceptablesalts thereof, which has advantages over prior art formulations.

The dosage form should accordingly provide pharmacologically activeplasma concentrations of the active ingredient3-(2-dimethylaminomethylcyclohexyl)phenol over an extended period,preferably for at least 12 h, (controlled release) and, in so doing, becharacterised by the smallest possible range of side-effects, inparticular with regard to nausea and/or vomiting. Pharmacokineticbehaviour should furthermore differ to a great extent from thepharmacokinetic behaviour of a comparison formulation without controlledrelease (active ingredient solution, succus, immediate release).

This object is achieved by the subject matter of the claims.

It has surprisingly been found that it is possible to produce a dosageform of the active ingredient 3-(2-dimethylaminomethylcyclohexyl)phenolor one of the pharmaceutically acceptable salts thereof which releasesthe active ingredient in controlled manner and, in so doing, hasadvantages over prior art dosage forms.

The invention relates to a dosage form for controlled release of theactive ingredient 3-(2-dimethylaminomethylcyclohexyl)phenol, preferably(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol, or one of thepharmaceutically acceptable salts thereof, which

-   (i) in vivo achieves the peak plasma level of the active ingredient    after 2 to 10 h,-   and/or-   (ii) in vitro, measured in accordance with the European    Pharmacopoeia with a paddle stirrer apparatus in buffer at a pH    value of 6.8 (preferably 900 ml), a temperature of 37° C. and 75 rpm    releases    -   after 0.5 hours 3.0 to 37 wt. %,    -   after 1 hour 5.0 to 56 wt. %,    -   after 2 hours 10 to 77 wt. %,    -   after 3 hours 15 to 88 wt. %,    -   after 6 hours at least 30 wt. %,    -   after 12 hours at least 50 wt. %,    -   after 18 hours at least 70 wt. % and    -   after 24 hours at least 80 wt. %-    of the active ingredient originally contained in the dosage form.

The following table shows particularly preferred release profiles of thedosage form according to the invention (no. 1 to no. 8):

after 1 2 3 4 5 6 7 8 [h] wt. % wt. % wt. % wt. % wt. % wt. % wt. % wt.% 0.5 5.0-34  6.0-33  7.0-32  9.0-31  11-30 13-30 15-29 17-28 1 12-5315-52 18-50 20-48 22-46 24-44 27-42 30-40 2 25-74 27-71 29-68 31-6533-62 36-60 39-58 42-56 3 33-85 36-82 39-79 42-76 45-73 48-71 50-6952-67 4 41-92 44-89 47-86 50-83 53-81 55-79 58-77 60-75 6 52-98 55-9758-96 60-94 63-92 66-90 69-88 72-86 8 >62 >65 >68 71-99 74-98 76-9878-97 80-97 12 >70 >73 >76 >79 >82 >84 >86 >88

The dosage form according to the invention releases the activeingredient 3-(2-dimethylaminomethylcyclohexyl)phenol, preferably afteroral administration, in delayed manner and is thus suitable foradministration at an interval of at least 12 h. The dosage formaccording to the invention accordingly permits pain therapy whichrequires the administration of the active ingredient3-(2-dimethylaminomethylcyclohexyl)phenol only once daily, for exampleat intervals of 24 h, or twice daily, preferably at intervals of 12hours, in order to ensure an adequate plasma concentration of the activeingredient.

It has here surprisingly been found that, in comparison withconventional dosage forms intended for oral administration of3-(2-dimethylaminomethylcyclohexyl)phenol, it is possible to achieve asignificant reduction in side-effects, in particular nausea and/orvomiting. This has the advantage of increasing the therapeutic range(ratio of the therapeutic dose to the toxic active ingredient dose) of3-(2-dimethylaminomethylcyclohexyl)phenol, as a result of which it ispossible inter alia to increase the active ingredient dose and thus alsotherapeutic efficacy.

FIG. 1 shows average plasma concentrations of the active ingredient3-(2-dimethylaminomethylcyclohexyl)phenol after oral administration ofdosage forms according to the invention with controlled release PR (A),PR (B) and PR (C) in comparison with a conventional dosage form(comparison formulation without controlled release, active ingredientsolution, succus, IR). In FIG. 1A, the y-axis is linear, while in FIG.1B it is logarithmic.

In a conventional dosage form without controlled release (immediaterelease IR, active ingredient solution, succus) it may usually beassumed that, very shortly after administration, the course of theplasma concentration/time curve is substantially solely determined bythe kinetics of metabolisation and excretion of the active ingredientfrom the body. Such kinetics vary from active ingredient to activeingredient (substance constant) but are virtually independent of theformulation of the dosage form.

In contrast, in a conventional dosage form with controlled release, itmay usually be assumed that the formulation of the dosage form has aninfluence on the course of the plasma concentration/time curve for aslong as active ingredient is still being released from the dosage form.Over this interval of time, the kinetics of resupply of the activeingredient from the dosage form and the kinetics of metabolisation andexcretion of the active ingredient which has already been released aresuperimposed on one another. However, from a certain point in time,release of the active ingredient from the dosage form has progressed sofar that almost no further active ingredient is supplied. The kineticsof resupply of the active ingredient from the dosage form then has atmost only a slight influence on the course of the plasmaconcentration/time curve. Instead, in this phase the course of theplasma concentration/time curve is substantially still only dominated bythe kinetics of metabolisation and excretion of the active ingredientfrom the body; accordingly, over this period of time, the course of theplasma concentration/time curve becomes similar to the course observedin dosage forms without controlled release.

However, as is clear from FIG. 1, in the dosage forms according to theinvention (PR (A), PR (B) and PR (C)), sometimes even many hours afteradministration, the course of the plasma concentration/time curve doesnot closely follow the course of the plasma concentration/time curve ofa comparison formulation without controlled release (active ingredientsolution, succus, IR). As is in particular clear from FIG. 1B, even manyhours after administration, the gradients in the terminal part of thecourse of the plasma concentration/time curve in the dosage formsaccording to the invention with controlled release (PR (A), PR (B) andPR (C)) are distinctly different from the gradient of the comparisonformulation without controlled release (the terminal run-outs of thecurves do not have a parallel course, but are instead a bundle ofcurves).

In the terminal elimination phase in the plasma concentration/timediagram with logarithmic linear regression, the negative gradient of theregression lines is defined as the rate constant λ_(z). The surprisingbehaviour of the dosage form with controlled release according to theinvention in comparison with a conventional dosage form withoutcontrolled release may therefore be identified by λ_(z) or the half-lifederived therefrom.

This surprising behaviour of the dosage form according to the inventionhas the advantage that, in vivo, the dosage form still has acontrolled-release action on the plasma concentration of the activeingredient at times at which, on the basis of the in vitro release ratedata, no further significant controlled-release action would beanticipated. The in vivo controlled-release action (measured plasmaconcentration) is accordingly enhanced relative to the in vitrocontrolled-release action (measured release values); it has asuperproportional action. The expected duration of action is accordinglyextended and compatibility is further improved in comparison with thesituation to be anticipated without this in vivo effect.

For the purposes of the description, “controlled” release of the activeingredient may, within the bounds of the invention, be delayed release(extended release), repeat action release, prolonged release orsustained release. Immediate active ingredient release (immediaterelease), such as is achieved for example with the assistance of anactive ingredient solution, should not be understood for the purposes ofthe description to mean controlled release of the active ingredient.

In a preferred embodiment of the dosage form according to the invention,the dosage form comprises a polymer matrix which releases preferably atleast a proportion of the entirety of the active ingredient contained inthe dosage form in delayed manner (matrix controlled-releaseformulation). To this end, at least this proportion of the activeingredient, preferably (1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenolor one of the pharmaceutically acceptable salts thereof, is presentembedded in the polymer matrix.

In another preferred embodiment of the dosage form according to theinvention, the dosage form comprises a film coating which releasespreferably at least a proportion of the entirety of the activeingredient contained in the dosage form in delayed manner (coatedcontrolled-release formulation).

It is also possible to combine a matrix controlled-release formulationwith a coated controlled-release formulation. However, according to theinvention, release of the active ingredient is preferably substantiallyexclusively controlled by a polymer matrix.

In a preferred embodiment, the dosage form according to the inventioncomprises a polymer matrix which preferably comprises one or morehydrophilic or hydrophobic, pharmaceutically acceptable polymers, forexample cellulose ethers, cellulose esters, polyethylene glycols (PEG),gums, (meth)acrylates, protein-derived material, fats, waxes, fattyalcohols and/or fatty acid esters. When hydrophilic polymers are used asmatrix former, it is preferred for the proportion by weight of thepolymer matrix to amount to 5.0 to 85 wt. %, preferably 20 to 60 wt. %,relative to the total weight of the dosage form according to theinvention.

The dosage form according to the invention preferably comprises apolymer matrix, in which at least a proportion of the active ingredient,preferably (1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol or one ofthe pharmaceutically acceptable salts thereof, is embedded, wherein thepolymer matrix is based on a cellulose ether and/or cellulose ester,which at a concentration of 2.0 wt. % in an aqueous solution at 20° C.has a viscosity, preferably determined by capillary viscosimetryaccording to the European Pharmacopoeia, in the range from 3,000 to150,000 mPa·s, preferably from 5,000 to 145,000 mPa·s, more preferablyfrom 10,000 to 140,000 mPa·s, still more preferably from 25,000 to135,000 mPa·s, most preferably from 50,000 to 130,000 mPa·s and inparticular from 80,000 to 120,000 mPa·s.

In a preferred embodiment of the dosage form according to the invention,the polymer matrix comprises at least one cellulose ether and/orcellulose ester selected from the group consisting of methylcellulose(MC), ethylcellulose (EC), hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) andhydroxypropylmethylcellulose (HPMC). Most preferred are HPMCs with aviscosity of approx. 100,000 mPa·s, measured in a 2 wt. % aqueoussolution at 20° C. Alternatively or additionally, the matrix may alsohave a content of polyethylene glycols (PEG) of 0 to 60 wt. %.

The proportion by weight of the polymer matrix is preferably in therange from 5.0 to 85 wt. %, more preferably from 10 to 50 wt. % and mostpreferably from 25 to 45 wt. %, relative to the total weight of thedosage form. When determining the proportion by weight, account ispreferably taken only of those polymers of the dosage form according tothe invention which form a matrix in which at least a proportion of theactive ingredient is embedded. Conventional polymeric auxiliaries, suchas for example microcrystalline cellulose, in contrast are not includedin the determination if they play virtually no part in matrix formation.

In a preferred embodiment of the dosage form according to the invention,the proportion by weight of the active ingredient, preferably(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol or one of thepharmaceutically acceptable salts thereof, is in the range from 0.5 to85 wt. %, more preferably from 5.0 to 50 wt. % and most preferably from15 to 35 wt. %, relative to the total weight of the dosage form.

In the dosage forms according to the invention, the active ingredientcontent is preferably between 0.5 and 85 wt. % and the content of thepolymer matrix is between 8.0 and 40 wt. %. Particularly preferreddosage forms are those having an active ingredient content of between3.0 and 70 wt. %, in particular between 8.0 and 66 wt. %, and a polymermatrix content of between 10 and 35 wt. %, in particular between 10 and30 wt. %, relative to the total weight of the pharmaceuticalcomposition.

The relative weight ratio of the polymer matrix to the activeingredient, preferably to(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol, or to one of thepharmaceutically acceptable salts thereof, is preferably in the rangefrom 3:1 to 1:10, more preferably from 2.5:1 to 1:8, still morepreferably from 2.2:1 to 1:5 and most preferably from 2:1 to 1:2.

In a particularly preferred embodiment of the dosage form according tothe invention, the polymer matrix comprises hydroxypropylmethylcellulosewhich at a concentration of 2.0 wt. % in an aqueous solution at 20° C.has a viscosity, preferably determined by capillary viscosimetryaccording to the European Pharmacopoeia, in the range from 50,000 to130,000 mPa·s, wherein simultaneously the proportion by weight ofhydroxypropylmethylcellulose is in the range from 15 to 35 wt. %,relative to the total weight of the dosage form.

The pharmaceutical dosage forms according to the invention mayfurthermore contain usual pharmaceutical auxiliary materials as furtherconstituents, such as for example

-   -   fillers, for example lactose, microcrystalline cellulose (MCC)        or calcium hydrogenphosphate, and/or    -   slip, lubricant and flow-control agents, for example talcum,        magnesium stearate, stearic acid and/or highly disperse silicon        dioxide,        wherein the total content thereof in the tablet is preferably        between 0 and 80 wt. %, more preferably between 5.0 and 65 wt.        %.

Such auxiliary materials are known to a person skilled in the art. Inthis connection, reference may for example be made to the full contentof H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik undangrenzende technische Gebiete, Editio Cantor Aulendorff, 2002.

The dosage form according to the invention preferably contains at leastone filler, wherein the relative weight ratio of the filler or the totalof all fillers to the polymer matrix is less than 6:1, more preferablyin the range from 5:1 to 1:2, still more preferably from 4:1 to 1:1.5and most preferably from 3:1 to 1:1.

In a preferred embodiment of the dosage form according to the inventionit contains a filler selected from the group consisting of

-   -   fillers soluble in an aqueous medium, for example lactose,    -   non-swelling fillers insoluble in an aqueous medium, for example        calcium hydrogenphosphate; and    -   swelling fillers insoluble in an aqueous medium, for example        microcrystalline cellulose.

The filler is preferably selected from the group consisting ofmicrocrystalline cellulose, calcium hydrogenphosphate and lactose.

The release profiles of the active ingredient, preferably(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol or one of thepharmaceutically acceptable salts thereof, from the dosage formaccording to the invention are preferably independent of the pH value asmay prevail physiologically during passage through the gastrointestinaltract. The release profiles at a pH value of the surroundings of 1.2 and6.8 are preferably both substantially identical to one another and alsoin comparison with release over pH value time profile from pH 1.2through pH 2.3 and through pH 6.8 up to pH 7.2.

The dosage form according to the invention contains3-(2-dimethylaminomethylcyclohexyl)phenol or one of the pharmaceuticallyacceptable salts thereof as active ingredient. The active ingredient mayhere be present as a mixture of two or more of the stereoisomers(enantiomers and/or diastereomers) thereof.3-(2-Dimethylaminomethylcyclohexyl)phenol may be present in the dosageform according to the invention not only as a mixture of all fourdiastereomers in any desired mixing ratio, but also as a mixture of twoor three of the four stereoisomers or in stereoisomerically pure form.In a preferred embodiment, the active ingredient is present as a racemiccompound of the (1R,2R)/(1S,2S) enantiomeric pair, wherein preferablyneither the (1R,2S), nor the (1S,2R) diastereomer is present or theproportion by weight thereof is less than 2.0 wt. %, relative to thetotal weight of the active ingredient.

Pharmaceutically acceptable salts of the active ingredient for thepurposes of the present invention are such salts of the activeingredient, which, when used pharmaceutically, are physiologicallycompatible, in particular for use in mammals and/or humans. Suchpharmaceutically acceptable salts may, for example, be formed withinorganic or organic acids. Examples of salts of inorganic acids whichmay be mentioned are: hydrochlorides, hydrobromides, sulfates,phosphates, hydrogenphosphates and dihydrogenphosphates. Examples ofsalts of organic acids which may be mentioned are: formates, acetates,propionates, fumarates, glutarates, pyruvates, malates, tartrates,benzoates, citrates, ascorbates, maleates, etc.

In a particularly preferred embodiment, the dosage form according to theinvention contains the stereoisomer(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol or one of thepharmaceutically acceptable salts thereof, wherein the enantiomericexcess thereof preferably amounts to at least 90% ee, more preferably atleast 95% ee, still more preferably at least 97% ee and in particular atleast 98% ee.

The active ingredient 3-(2-dimethylaminomethylcyclohexyl)phenol may bepresent not only as such, i.e. as the free base, but also in the form ofa pharmaceutically acceptable salt, for example as the hydrochloride.Production of the hydrochlorides is known, for example, from DE-A 195 25137. Prior art methods are known for converting the hydrochloride intothe free base or into another pharmaceutically acceptable salt. Methodsfor separating the enantiomers or diastereomers are also sufficientlywell known in the prior art. The diastereomers may, for example, beseparated by HPLC and the enantiomers by HPLC on chiral stationaryphases.

In addition to the active ingredient3-(2-dimethylaminomethylcyclohexyl)phenol or one of the pharmaceuticallyacceptable salts thereof, the dosage form according to the invention maycontain further pharmaceutically active substances. Preferably, however,the dosage form according to the invention contains only3-(2-dimethylaminomethylcyclohexyl)phenol, preferably(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol or one of thepharmaceutically acceptable salts thereof, and otherwise no furtherpharmaceutically active substances.

Preferred embodiments of the dosage form according to the invention (no.1 to no. 5) comprise the following constituents in the followingquantities (percentages are in each case relative to the total weight ofthe dosage form):

wt. % Constituent 1 2 3 4 5 Active ingredient, preferably (1R,2R)-3-(2-1.0-50  2.5-45  5.0-41  15-35 20-30 dimethylaminomethylcyclohexyl)phenolCellulose ether or cellulose ester, preferably 5.0-75  7.5-60  9.0-50 15-45 25-40 MC, EC, HEC, HPC, CMC or HPMC Filler, preferablymicrocrystalline cellulose, 10-90 20-75 30-66 35-60 40-55 calciumhydrogenphosphate or lactose Flow-control agent, preferably highlydisperse   0-5.0   0-2.5   0-1.0 0.1-1.0 0.2-0.8 silicon dioxide Slipagents, preferably magnesium stearate   0-5.0   0-2.5   0-1.0 0.1-1.00.2-0.8

Further constituents of the dosage form according to the invention maybe optionally digestible long-chain (i.e. with 8 to 50 C atoms,preferably 12 to 40 C atoms) unsubstituted or substituted hydrocarbons,such as for example fatty alcohols, fatty acid glyceryl esters, mineraland vegetable oils, as well as waxes, wherein hydrocarbons with amelting point of between 25° and 90° C. are preferred. In particular,fatty alcohols are preferred, most particularly lauryl alcohol, myristylalcohol, stearyl alcohol, cetyl alcohol and cetyl stearyl alcohol. Thecontent thereof in the dosage form is preferably 0 to 20 wt. %.

The dosage form according to the invention is characterised byadvantageous pharmacokinetic parameters.

For the purposes of the description, the pharmacokinetic parameters,which may be determined from the blood plasma concentrations of3-(2-dimethylaminomethylcyclohexyl)phenol, are defined as follows:

τ Dose range C_(max) maximum measured plasma concentration of the activeingredient after single administration (≡average peak plasma level)C_(min) minimum measured plasma concentration of the active ingredientafter single administration C_(av) average plasma concentration of theactive ingredient after${{single}\mspace{14mu} {administration}\mspace{11mu} \text{:}\mspace{11mu} C_{av}} = \frac{{AUC}_{\tau}}{\tau}$t_(max) interval of time from administration of the active ingredientuntil C_(max) is reached t_(lag), t(0) interval of time fromadministration until the first detectable plasma concentration of theactive ingredient (lag time) AUC_(τ) total area of the plasmaconcentration/time curve during τ AUC_(0-t) total area of the plasmaconcentration/time curve from administration until the final measuredvalue AUC_(t-∞) subarea of the plasma concentration/time curve from thefinal measured value extrapolated to infinity AUC total area of theplasma concentration/time curve including the subarea from the finalmeasured value extrapolated to infinity AUC %_(extr) subarea of theplasma concentration/time curve from the final measured valueextrapolated to infinity in percent λ_(z) rate constant of the terminalelimination phase, defined as the negative gradient of the regressionlines with logarithmic linear regression t_(1/2, z)${{half}\text{-}{life}\mspace{14mu} {during}\mspace{14mu} {the}\mspace{14mu} {terminal}\mspace{14mu} {elimination}\mspace{14mu} {phase}\text{:}\mspace{14mu} t_{{1/2},z}} = \frac{\ln (2)}{\lambda_{z}}$HVD half value duration, defined as the time interval over which plasmaconcentration is greater than 50% of C_(max) MRT mean residence time,defined as the ratio of AUMC (area under the “first moment curve”) andAUC (cf. M. Gibaldi, D. Perrier, J Pharm. Sci. 1982, 71(4), 474-5) CL/f${{total}\mspace{14mu} {clearance}\mspace{14mu} {after}\mspace{14mu} {oral}\mspace{14mu} {administration}\mspace{11mu} \text{:}\mspace{11mu} {{CL}/f}} = \frac{Dose}{AUC}$V_(z)/f apparent distribution volume during the terminal disposition${{phase}\mspace{14mu} {after}\mspace{14mu} {oral}\mspace{14mu} {administration}\mspace{11mu} \text{:}\mspace{14mu} {V_{z}/f}} = \frac{Dose}{{AUC} \cdot \lambda_{z}}$PTF peak to trough fluctuation over an administration period:${{PTF}\mspace{11mu} \%} = {100\frac{C_{\max} - C_{\min}}{C_{av}}}$

The above parameters are in each case stated as mean values of theindividual values for all investigated patients/test subjects.

A person skilled in the art knows how the pharmacokinetic parameters ofthe active ingredient 3-(2-dimethylaminomethylcyclohexyl)phenol may becalculated from the measured concentrations of the active ingredient inthe blood plasma. In this connection, reference may be made, forexample, to Willi Cawello (ed.) Parameters for Compartment-freePharmacokinetics, Shaker Verlag Aachen (1999).

After preferably oral administration of the dosage form according to theinvention, in vivo the average peak plasma level (C_(max)) is on averagepreferably reached after t_(max) 2 to 10 h, more preferably after 3 to 8h, still more preferably after 3.5 h to 6 h, most preferably after 4.0to 5.5 h and in particular after 4.2 to 5.2 h.

The average value for MRT after preferably oral administration of thedosage form according to the invention in vivo is preferably more than7.5 h, more preferably more than 8.0 h, still more preferably more than9.0 h; it is most preferably in the range from 10.0 to 25.0 h and inparticular in the range from 11.0 to 20.0 h.

The average value for HVD after preferably oral administration of thedosage form according to the invention in vivo is preferably more than5.0 h, more preferably more than 6.0 h, still more preferably more than7.0 h; it is most preferably in the range from 8.0 to 20.0 h and inparticular in the range from 9.0 to 18.0 h.

The average value for λ_(z) at identical dose is preferably lower thanin a comparison formulation without controlled release. The averagevalue for λ_(z) after preferably oral administration of the dosage formaccording to the invention in vivo is preferably less than 0.125 h⁻¹,more preferably less than 0.122 h⁻¹, still more preferably less than0.118 h⁻¹; it is most preferably in the range from 0.050 to 0.115 h⁻¹and in particular in the range from 0.060 to 0.112 h⁻¹.

The average value for t_(1/2,z) at identical dose is preferably higherthan in a comparison formulation without controlled release. The averagevalue for t_(1/2,z) after preferably oral administration of the dosageform according to the invention in vivo is preferably more than 5.7 h,more preferably more than 6.0 h, still more preferably more than 6.2 h;it is most preferably in the range from 6.4 h to 20.0 h and inparticular in the range from 6.6 h to 15.0 h.

A “comparison formulation without controlled release” is taken for thepurposes of the description to mean an immediate release formulation ofthe active ingredient, for example a succus, for example an activeingredient solution or active ingredient dispersion with identicaldosage. In a preferred embodiment, this is taken to mean an activeingredient solution, 1 ml of which contains the following constituents:

-   10.0 mg 3-(2-dimethylaminomethylcyclohexyl)phenol or an equivalent    dose of one of the pharmaceutically acceptable salts thereof-   7.0 mg sodium chloride, Ph.Eur., for parenteral use-   0.5 mg sodium citrate.2H₂O, Ph.Eur., for parenteral use-   985.5 mg water for injection, Ph.Eur.*

In another preferred embodiment, a “comparison formulation withoutcontrolled release” is taken to mean a capsule formulation comprisingthe auxiliary substances microcrystalline cellulose, low-substitutedhydroxypropylcellulose, magnesium stearate and silicon dioxide,preferably of the following composition:

-   30 mg 3-(2-dimethylaminomethylcyclohexyl)phenol or an equivalent    dose of one of the pharmaceutically acceptable salts thereof,-   231 mg microcrystalline cellulose, PH102, Ph.Eur.,-   72 mg low-substituted hydroxypropylcellulose, NF (L-HPC, grade LH    11),-   18 mg magnesium stearate, Ph.Eur., and-   9 mg highly disperse silicon dioxide, Ph.Eur.;-   Total weight: 360 mg, preferably in a hard gelatine capsule, size    0el.

At dose D of the active ingredient, the average value for C_(max)/Dafter preferably oral administration of the dosage form according to theinvention in vivo is preferably 7.0 10⁻⁵ l⁻¹≦C_(max)/D≦1.05 10⁻³ l⁻¹,more preferably 8.0 10⁻⁵ l⁻¹≦C_(max)/D≦1.0 10⁻³ l⁻¹, still morepreferably 9.0 10⁻⁵ l⁻¹≦C_(max)/D≦9.0 10⁻⁴ l⁻¹, most preferably 1.0 10⁻⁴l⁻¹≦C_(max)/D≦8.0 10⁻⁴ l⁻¹, and in particular 2.0 10⁻⁴ l⁻¹≦C_(max)/D≦7.010⁻⁴ l⁻¹.

The average value for C_(max)/AUC after preferably oral administrationof the dosage form according to the invention in vivo is preferablybetween 0.150 and 0.010 h⁻¹, more preferably between 0.125 and 0.020h⁻¹, still more preferably between 0.100 and 0.030 h⁻¹, most preferablybetween 0.095 and 0.040 h⁻¹ and in particular between 0.090 and 0.050h⁻¹. The value for C_(max)/AUC may be regarded as a surrogate forabsorption rate.

In the case of twice daily administration, preferably at intervals of 12h, the average value for PTF is preferably <80%, more preferably ≦75%,still more preferably ≦70%, most preferably ≦65% and in particular ≦60%.

The dosage form according to the invention contains the activeingredient 3-(2-dimethylaminomethylcyclohexyl)phenol, preferably(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol, as such and/or as apharmaceutically acceptable salt in a quantity of conventionally 2.5 to800 mg, in particular 5 to 400 mg, very particularly preferably 10 to250 mg (weight relative to 3-(2-dimethylaminomethylcyclohexyl)phenol ashydrochloride) per dosage unit, wherein the release behaviour of thedosage form according to the invention is virtually unaffected by theexact quantity of active ingredient, provided that the above-statedcontent limits are observed.

A preferred embodiment of the dosage form according to the invention isformulated for oral or rectal administration, preferably once or twicedaily. If taken once or twice daily, a pharmaceutical dosage formaccording to the invention reliably achieves good therapeuticeffectiveness in patients with chronic, severe pain.

The pharmaceutical dosage forms according to the invention may assumethe form of both simple tablets and coated tablets, for example filmtablets or sugar-coated tablets. The tablets are conventionally round orbiconvex; oblong tablet shapes, which allow the tablet to be divided,are also possible. Granules, spheroids, pellets or microcapsules arealso possible, which are packaged in sachets or capsules or may becompressed to form disintegrating tablets.

It is also possible, in addition to or as an alternative to the delayedrelease matrix in the pharmaceutical dosage form, to use a coating whichcontrols release of the active ingredient. The active ingredient, whichis preferably, but not necessarily, embedded in a polymer matrix, andoptionally further pharmaceutical auxiliaries, such as for instancebinders, fillers, slip, lubricant and flow-control agents, may bepresent in this case and be covered or coated with a material whichcontrols and/or modulates delayed release of the active ingredient in anaqueous medium. Suitable coating materials are, for example,water-insoluble waxes and polymers, such as polymethacrylates (Eudragitor the like) or water-insoluble celluloses, in particularethylcellulose. The coating material may optionally also containwater-soluble polymers, such as polyvinylpyrrolidone, water-solublecelluloses, such as hydroxypropylmethylcellulose orhydroxypropylcellulose, other water-soluble agents, such as Polysorbate80, or hydrophilic pore formers, such as polyethylene glycol, lactose ormannitol.

One or more coating layers may be used for the coated dosage forms,preferably tablets. Known hydroxypropylmethylcelluloses with a lowviscosity of approx. 1.0 to 100 mPa·s and a low molecular weight of<10,000 g mol⁻¹ (for example Pharmacoat 606 with a viscosity of 6.0mPa·s in a 2.0 wt. % aqueous solution at 20° C.), which have virtuallyno or only a slight effect on the release profile of the medicamentaccording to the invention, are suitable as coating materials.

Diffusion coatings known to a person skilled in the art, for examplebased on swellable, but water-insoluble poly(meth)acrylates, modulatethe delay to active ingredient release from pharmaceutical dosage formsaccording to the invention. The core, which contains the activeingredient and releases it preferably in delayed manner, with an activeingredient content preferably of between 0.5 and 85 wt. %, particularlypreferably of between 3.0 and 70 wt. % and very particularly preferablyof between 8.0 and 66 wt. %, may be covered with additional activeingredient, which is released in undelayed manner as an initial dose, byvarious methods known to a person skilled in the art, for example pancoating, spraying of solutions or suspensions or by powder applicationmethods, without this being absolutely essential for the desired delayedrelease simultaneously accompanied by rapid loading of the activeingredient for rapid pain relief on first administration of thepharmaceutical formulation according to the invention.

Further embodiments of the dosage form according to the invention aremultilayer and jacketed tablets in which the active ingredient, in oneor more layers of the multilayer tablet with an active ingredientcontent of preferably between 0.5 and 85 wt. %, particularly preferablybetween 3.0 and 70 wt. % and very particularly preferably between 8.0and 66 wt. % or in the core of the jacketed tablet with an activeingredient content of preferably between 0.5 and 85 wt. %, particularlypreferably between 3.0 and 70 wt. % and very particularly preferablybetween 8.0 and 66 wt. % is released in controlled manner by a polymermatrix and release of the active ingredient in one or more layers of themultilayer tablet or the outer jacket layer of the jacketed tabletsproceeds in undelayed manner. Multilayer and jacketed tablets maycontain one or more coatings which contain no active ingredient.

The dosage forms according to the invention may, for example, beproduced by the following general method:

The constituents of the dosage form (active ingredient, polymers forforming the polymer matrix [matrix formers] and optional constituents)are weighed out in succession and then screened on a conventionalscreening machine. The Quadro Comil U10 screening machine may be usedfor this purpose, for example, a normal screen size being approx. 0.813mm. The screened composition is then mixed in a container mixer, forexample in a Bohle container mixer; typical operating conditions are:duration approx. 15 min±45 s at a rotational speed of 20±1 rpm. Theresultant powder mixture is then pressed in a tabletting press to form atablet. A Korsch EK0 tabletting press with a 10 mm diameter round,biconvex punch may for example be used for this purpose. Alternatively,the powder mixture may also be compacted and the compression mouldingssubsequently screened (Comil 3 mm abrasive cutting screen followed by1.2 mm round hole screen), the resultant granular product then beingpressed as described above with the addition of lubricant (for examplemagnesium stearate), for example on an EK0 tabletting press with 10 mmround punches. Granulation may also be performed by wet granulationbased on aqueous or organic solvents; aqueous solvents with or withoutsuitable binders are preferred. The production method canstraightforwardly be adapted to particular requirements and the desireddosage form in accordance with methods well known in the prior art.

The production of pharmaceutical dosage forms according to the inventionis characterised by elevated reproducibility of the releasecharacteristics of the compositions obtained, which contain3-(2-dimethylaminomethylcyclohexyl)phenol or a pharmaceuticallyacceptable salt thereof. The release profile of the dosage formsaccording to the invention has proven to be stable over a period ofstorage of at least one year under conventional storage conditions inaccordance with the ICH Q1AR Stability Testing Guideline.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising the active ingredient3-(2-dimethylaminomethylcyclohexyl)phenol or one of the pharmaceuticallyacceptable salts thereof, preferably(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol, as such and/or as apharmaceutically acceptable salt, and a cellulose ether or celluloseester which, at a concentration of 2.0 wt. % in an aqueous solution at20° C. has a viscosity in the range from 3,000 to 150,000 mPa·s.

The composition according to the invention is suitable for producing thedosage form according to the invention.

In a preferred embodiment of the composition according to the invention,the cellulose ether or cellulose ester is selected from the groupconsisting of methylcellulose, ethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose andhydroxypropylmethylcellulose.

Further preferred embodiments of the cellulose ether or cellulose esterare listed above in connection with the explanation of the dosage formaccording to the invention and also apply correspondingly for thecomposition according to the invention.

The present invention also provides the use of3-(2-dimethylaminomethylcyclohexyl)phenol or one of the pharmaceuticallyacceptable salts thereof for producing an above-described dosage form oran above-described composition for combatting pain. The pain ispreferably selected from the group consisting of acute pain and chronicpain, in particular inflammatory pain or neuropathic pain, wherein thepain may be weak, moderately severe, severe or extreme.

The combatting of pain is preferably accompanied by a significantreduction in the side-effect nausea and/or vomiting in comparison with adosage form without controlled release. Administration preferablyproceeds orally.

The present invention also provides the use of the active ingredient3-(2-dimethylaminomethylcyclohexyl)phenol or one of the pharmaceuticallyacceptable salts thereof for producing a dosage form with controlledactive ingredient release for combatting pain with a significantreduction in the side-effect nausea and/or vomiting in comparison with adosage form without controlled release. Administration preferablyproceeds orally. The pain is preferably selected from acute pain andchronic pain.

The present invention also provides a method for combatting paincomprising the administration of a pharmaceutically active quantity ofthe active ingredient 3-(2-dimethylaminomethylcyclohexyl)phenol or oneof the pharmaceutically acceptable salts thereof to a patient, whereinthe peak plasma level of the active ingredient is reached after 2 to 10h. Administration preferably proceeds orally. The pain is preferablyselected from acute pain and chronic pain.

The present invention also provides a method for combatting paincomprising the administration of a dosage form with controlled releasecontaining a pharmaceutically active quantity of the active ingredient3-(2-dimethylaminomethylcyclohexyl)phenol or one of the pharmaceuticallyacceptable salts thereof to a patient with a significant reduction inthe side-effect nausea and/or vomiting in comparison with a dosage formwithout controlled release. Administration preferably proceeds orally.The pain is preferably selected from acute pain and chronic pain.

The following Examples serve to illustrate the present invention andpreferred exemplary embodiments, but should not be interpreted aslimiting.

EXAMPLE 1

Matrix tablets with the following composition per tablet

mg wt. % (1R,2R)-3-(2-Dimethylaminomethylcyclohexyl)phenol 60 25Hydroxypropylmethylcellulose, 100,000 mPa · s 100 41.7 Microcrystallinecellulose (Avicel PH 102 from FMC) 77.5 32.3 Highly disperse silicondioxide 1.25 0.5 Magnesium stearate 1.25 0.5 Total quantity 240 100were produced in the following manner in a batch size of 1000 tablets:

All the constituents were weighed out and screened in a Quadro Comil U10screening machine using a screen size of 0.813 mm, mixed in a containermixer (Bohle LM 40) for 15 min±15 s at a rotational speed of 20±1 rpmand pressed on a Korsch EK0 eccentric press to form biconvex tabletswith a diameter of 10 mm, a radius of curvature of 8 mm and an averagetablet weight of 240 mg.

In vitro release was determined using the Ph.Eur. paddle method at 75rpm in 900 ml of pH 6.8 buffer to Ph.Eur. at 37° C. and with detectionby UV spectrometry and is stated in the following table.

Time Total quantity of active [min] ingredient released [%] 0 0 30 22 6033 120 47 180 57 240 65 360 77 480 85 600 91 720 95

EXAMPLE 2

Matrix tablets with the following composition per tablet

A B C D mg wt. % mg wt. % mg wt. % mg wt. % (1R,2R)-3-(2-Dimethylamino-15 6 40 16 80 32 100 40 methylcyclohexyl)phenolHydroxypropylmethylcellulose, 70 28 70 28 70 28 70 28 100.000 mPa · sMicrocrystalline cellulose 162.5 65 137.5 55 97.5 39 77.5 31 Highlydisperse silicon dioxide 1.25 0.5 1.25 0.5 1.25 0.5 1.25 0.5 Magnesiumstearate 1.25 0.5 1.25 0.5 1.25 0.5 1.25 0.5 Total quantity 250 100 250100 250 100 250 100were produced in a manner similar to the method stated in Example 1.

In vitro release was determined as in Example 1.

Time Total quantity of active ingredient released [%] [min] A B C D 0 00 0 0 30 27 23 20 19 60 37 33 32 31 120 51 48 48 47 180 60 58 60 59 24068 68 69 69 360 81 81 82 83 480 90 89 90 92 600 96 95 95 96 720 100 10098 99

EXAMPLE 3

Matrix tablets with the following composition per tablet

A B C mg wt. % (1R,2R)-3-(2- (1R,2R)-3-(2- (1R,2R)-3-(2- 80 32Dimethylaminomethyl- Dimethylaminomethyl- Dimethylamino-cyclohexyl)phenol cyclohexyl)phenol methylcyclo- hexyl)phenolHydroxypropylmethyl- Hydroxypropylmethyl- Hydroxypropylmethyl- 70 28cellulose, cellulose, cellulose, 100,000 mPa · s 100,000 mPa · s 100,000mPa · s Microcrystalline Calcium Lactose 97.5 39 cellulosehydrogenphosphate monohydrate Highly disperse silicon Highly dispersesilicon Highly disperse silicon 1.25 0.5 dioxide dioxide dioxideMagnesium stearate Magnesium stearate Magnesium stearate 1.25 0.5 Totalquantity Total quantity Total quantity 250 100were produced in a batch size of 75 tablets in a manner similar to themethod stated in Example 1.

In vitro release was determined as in Example 1.

Time Total quantity of active ingredient released [%] [min] A B C 0 0 00 30 19 21 21 60 31 32 33 120 47 48 49 180 58 59 59 240 67 67 68 360 7878 78 480 85 84 84 600 89 88 88 720 92 90 90

EXAMPLE 4

Matrix tablets with the following composition per tablet

mg wt. % (1R,2R)-3-(2-Dimethylaminomethylcyclohexyl)phenol 40 16Hydroxypropylmethylcellulose, 100,000 mPa · s 70 28 Microcrystallinecellulose 137.5 55 Highly disperse silicon dioxide 1.25 0.5 Magnesiumstearate 1.25 0.5 Total quantity 250 100were produced in a batch size of 100 tablets in a manner similar to themethod stated in Example 1.

In vitro release was determined under the following conditions:

-   (A): as described in Example 1;-   (B): application of Ph.Eur. paddle method at 75 rpm in 900 ml pH 1.2    buffer to USP 22 at 37° C. and with detection by UV spectrometry;-   (C): application of Ph.Eur. paddle method at 75 rpm, a pH of 1.2    being established from 0-30 min, a pH of 2.3 from 30-120 min, a pH    of 6.5 from 120-180 min and a pH of 7.2 for the remainder of the    test period.

The table states the results for the various test conditions:

Time Total quantity of active ingredient released [%] [min] A B C 0 0 00 30 19 18 18 60 32 31 32 120 48 46 47 180 60 59 60 240 68 67 67 360 7978 77 480 87 86 84 600 92 92 90 720 95 95 94

EXAMPLE 5

Matrix tablets with the following composition per tablet

mg wt. % (1R,2R)-3-(2-Dimethylaminomethylcyclohexyl)phenol 80 32Hydroxypropylmethylcellulose 100,000 mPa · s 70 28 Microcrystallinecellulose 97.5 39 Highly disperse silicon dioxide 1.25 0.5 Magnesiumstearate 1.25 0.5 Total quantity 250 100were produced in a batch size of 100 tablets in a manner similar to themethod stated in Example 1. Press-moulding was carried out withdifferent pressing forces, such that tablets with the following breakingstrengths were obtained:

(A) 60 N, (B) 80 N, (C) 100 N, (D) 150 N.

In vitro release was determined as in Example 1.

Time Total quantity of active ingredient released [%] [min] A B C D 0 00 0 0 30 18 18 20 20 60 31 31 32 30 120 49 48 49 45 180 61 60 61 56 24069 68 69 64 360 80 80 81 77 480 87 87 88 85 600 91 91 92 90 720 93 94 9493

EXAMPLE 6

Matrix tablets with the following composition per tablet

A B C mg wt. % (1R,2R)-3-(2- (1R,2R)-3-(2- (1R,2R)-3-(2- 40 16Dimethylaminomethyl- Dimethylaminomethyl- Dimethylaminomethyl-cyclohexyl)phenol cyclohexyl)phenol cyclohexyl)phenolHydroxypropylmethyl- Hydroxypropylmethyl- Hydroxypropylmethyl- 70 28cellulose, 90SH, cellulose, 60SH, cellulose, 65SH, 15,000 mPa · s 4,000mPa · s 4,000 mPa · s Microcrystalline Calcium Lactose monohydrate 137.555 cellulose hydrogenphosphate Highly disperse silicon Highly dispersesilicon Highly disperse silicon 1.25 0.5 dioxide dioxide dioxideMagnesium stearate Magnesium stearate Magnesium stearate 1.25 0.5 Totalquantity Total quantity Total quantity 250 100were produced in a batch size of 200 tablets in a manner similar to themethod stated in Example 1.

In vitro release was determined as in Example 1.

Time Total quantity of active ingredient released [%] [min] A B C 0 0 00 30 19 22 21 60 34 35 33 120 52 51 47 180 65 62 57 240 73 69 65 360 8379 75 480 90 84 82 600 92 88 86 720 94 90 89

EXAMPLE 7

Matrix tablets with the following composition per tablet

[mg] mg wt. % (1R,2R)-3-(2-Dimethylamino- 209.64 38.12methylcyclohexyl)phenol Hypromellose 15,000 mPa · s 60.00 10.91 Lactose,type 200 268.36 48.79 Colloidal anhydrous silicon 6.00 1.09 dioxideMagnesium stearate 6.00 1.09 Weight of tablet core 550.00 100.00were produced in a batch size of 1,000 tablets. To this end, all thetablet constituents were weighed out, screened through a 0.315 mmscreen, mixed, granulated with water in a Kenwood mixer, pressed througha 1 mm screen, dried at 50° C. in a Hoirden drying cabinet andpress-moulded on a Korsch EK0 eccentric tablet press with 7×17 mm oblongpunches [to form tablets] weighing 550 mg per tablet.

The tablets exhibited the following in vitro release properties:

Time Total quantity of active [min] ingredient released [%] 0 0 30 16240 61 480 92

EXAMPLE 8

a) Film coated tablets having the following composition per tablet

[mg] PR (A) PR (B) PR (C) (1R,2R)-3-(2-Dimethylamino- 60.00 60.00 60.00methylcyclohexyl)phenol Hypromellose 100,000 mPa · s 50.00 100.00 200.00(Shin-Etsu) Microcrystalline cellulose 137.50 87.50 85.00 (Avicel 102,FMC) Highly disperse silicon dioxide 1.25 1.25 2.50 Magnesium stearate1.25 1.25 2.50 Weight of tablet core 250.00 250.00 350.00were produced in a batch size of 1,000 tablets. To this end, all thetablet core constituents were weighed out, screened through a 0.315 mmscreen, mixed and press-moulded on a Fette P1200 rotary tablet presswith 10 mm punches and a radius of curvature of 8 mm. The tablets(formulation A and B) were then film-coated with an aqueous lacquersuspension (approx. 29% solids content) prepared from hypromellose 6mPa·s, Macrogol 6000, propylene glycol, talcum, titanium dioxide andpurified water, until the tablet weight had risen by 12 mg.

The film coated tablets exhibited the following in vitro release values:

Time Total quantity of active ingredient released [%] [min] PR (A) PR(B) PR (C) 0 0 0 0 30 22 18 14 180 65 240 62 47 360 85 480 84 720 80

As the above table shows, 80% of the active ingredient in formulationsPR (A), PR (B) and PR (C) were released in vitro after approx. 360 min,480 min and 720 min respectively.

b) In an open, randomised phase 1 four-way crossover study, thepharmacokinetic parameters for these three dosage forms according to theinvention exhibiting different release behaviour [prolonged release, PR(A), PR (B) and PR (C)] were determined in vivo and compared with anactive ingredient solution [immediate release, IR] as a referenceformulation. 1 ml of the IR active ingredient solution contained:

10.0 mg (1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol 7.0 mg sodiumchloride, Ph. Eur., for parenteral use 0.5 mg sodium citrate · 2H₂O, Ph.Eur., for parenteral use 985.5 mg water for injection, Ph. Eur.*

Production proceeded in accordance with the standard procedure forsolutions for injection; the solution was packaged in 1 ml portions inampoules.

A dose D of 60 mg of (1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenolwas administered to each of 8 volunteer female test subjects and theplasma concentration of the active ingredient was measured over 32hours.

Quantitative analysis of the concentration of(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol in the blood plasmawas carried out using O-desmethyltramadol (M1) as internal standard. Theactive ingredients were extracted from the samples by liquid-liquidextraction with tert.-butyl methyl ether. The extracts were analysedwith HPLC by fluorometric detection. The calibration curves exhibitedsignal linearity in the plasma concentration range from 0.23 ng/ml to 92ng/ml.

The results are shown in FIGS. 1A and 1B. FIG. 1A shows a linearrepresentation of plasma concentration (y-axis), FIG. 1B a logarithmicrepresentation.

Pharmacokinetic parameters were calculated by noncompartmentalisedanalysis using the validated software package MODUNA, which wasdeveloped by Grunenthal GmbH.

The calculations were carried out using all available decimal placeswithout rounding.

The first subarea from administration until the first valid plasmaconcentration was calculated, depending on the type of administration,by extrapolating a concentration value C_(tdose) to the time ofadministration tdose. If t_(lag) was >0 h, the first subarea wascalculated from t_(lag).

AUC was calculated by summation from the subarea AUC_(0-t) (area underthe concentration/time curve with measured concentrations above thedetection limit) and the residual area AUC_(t-∞) (=ĉ_(t)/λ_(z)), inwhich ĉ_(t) is the plasma concentration estimated on the basis of alogarithmic linear regression at the time of the final measurement atwhich a plasma concentration which was still above the detection limitwas determined.

AUC_(0-∞)T was calculated by numerical integration using the trapeziumrule (Gibaldi and Perrier, 1982). The linear trapezium rule was appliedup to C_(max) and thereafter the logarithmic trapezium rule. If two ormore plasma concentration maxima were observed, C_(max) was determinedfor the first maximum.

The rate constant of the terminal elimination phase λ_(z) was determinedby logarithmic linear regression of the terminal phase of the plasmaconcentration curves (Cawello, 1999). The λ_(z) time interval [h] forthe regression was defined according to the following table:

Female test subject 1 2 3 4 5 6 7 8 PR(A) 10-32 10-32 10-32 10-32 10-3210-32 10-32 10-32 PR(B) 10-32 10-32 10-32 10-32 10-32 10-32 10-32 10-32PR(C) 16-32 10-28 10-32 10-32 10-32 13-32 13-32 10-32 IR 20-32 10-3210-32 10-32 10-32 10-32 20-32 13-28

When determining the half value duration HVD, the time at which theplasma concentration was 50% of C_(max) was determined by linearinterpolation.

The following table summarises the pharmacokinetic parameters calculatedfrom the measured plasma concentrations:

PR (A) PR (B) PR (C) IR [Comparison] D = 60 mg Mean CV [%] Mean CV [%]Mean CV [%] Mean CV [%] t_(max) [h] 5.00 18.5 4.50 23.8 4.75 27.0 1.2537.0 t_(1/2, z) [h] 6.68 23.5 7.44 27.7 12.10 32.5 5.69 25.0 MRT [h]11.75 11.1 13.47 19.1 19.59 28.5 7.28 16.7 HVD [h] 9.40 23.1 12.05 24.515.07 39.0 4.78 42.8 λ_(z) [h⁻¹] 0.109 23.4 0.099 26.2 0.063 33.9 0.12822.2 V(z)/f [l] 1,569 40.8 1,665 29.5 2,817 52.7 1,102 26.1 CL/f [mlmin⁻¹] 2,708 34.9 2,747 44.0 2,800 54.7 2,392 43.7 AUC_(0-t) [h ng ml⁻¹]343 39.3 341 41.7 310 42.9 404 32.5 AUC [h ng m⁻¹] 359 38.6 369 41.4 38444.3 411 33.0 C_(max) [ng ml⁻¹] 32.2 58.3 26.8 65.6 19.7 38.0 64.2 40.9C_(max)/D [l⁻¹] 5.37 10⁻⁴ — 4.48 10⁻⁴ — 3.28 10⁻⁴ — 1.07 10⁻³ —C_(max)/AUC [h⁻¹] 0.090 — 0.073 — 0.051 — 0.156 —

The controlled-release formulations (prolonged release PR (A), PR (B)and PR (C)) which under in vitro conditions release 80% of the activeingredient after approx. 360 min, 480 min and 720 min respectively, alsoexhibited an increasing delayed-release action in vivo in humans.

While the average value for C_(max) on administration of the activeingredient solution was 64.2 ng/ml (comparison, immediate release, IR),it declined to 32.2 ng/ml (PR(A)), 26.8 ng/ml (PR(B)) and 19.7 ng/ml(PR(C)) on administration of the formulations according to theinvention.

The average value for t_(max) was similar for all three formulationsaccording to the invention and was in the range from 4.5 to 5.0 h, butwas clearly delayed in comparison with administration of the activeingredient solution (1.25 h).

The average half value duration HVD increased from 4.78 h onadministration of the active ingredient solution to 9.40 h (PR (A)),12.05 (PR (B)) and 15.07 h (PR (C)). The results for the mean residencetime confirmed this trend with increases from 7.28 h on administrationof the active ingredient solution to up 19.59 h (PR (C)).

The half-life during the terminal elimination phase increased from 5.69h on administration of the active ingredient solution to 6.68 h (PR(A)), 7.44 (PR (B)) and 12.10 h (PR (C)). An adequate delayed-releaseaction in comparison with a immediate release formulation (activeingredient solution, succus, IR) is characterised by halving C_(max) ordoubling HVD while simultaneously increasing t_(1/2,z), ideally withoutin so doing changing the AUC.

In one study, the PTF % individual values after twice dailyadministration were between 49% and 88% in a dose range from 160 to 400mg daily dose. The average values within the dose groups were between57% and 64%.

c) It has been found in clinical testing that, in comparison withconventional dosage forms intended for oral administration of3-(2-dimethylaminomethylcyclohexyl)phenol, it is possible to achieve asignificant reduction in side-effects, in particular nausea and/orvomiting.

This has inter alia the advantage that the therapeutic range (ratio ofthe therapeutic dose to the toxic active ingredient dose) of3-(2-dimethylaminomethylcyclohexyl)phenol is increased.

1-33. (canceled)
 34. A dosage form for controlled release of the activeingredient 3-(2-dimethylaminomethylcyclohexyl)phenol or apharmaceutically acceptable salt thereof, wherein said dosage formachieves in vivo a peak plasma level of said active ingredient after 2to 10 hours.
 35. A dosage form for controlled release of the activeingredient 3-(2-dimethylaminomethylcyclohexyl)phenol or apharmaceutically acceptable salt thereof, wherein said dosage formreleases in vitro, after 0.5 hour 3.0 to 37 wt. %, after 1 hour 5.0 to56 wt. %, after 2 hours 10 to 77 wt. %, after 3 hours 15 to 88 wt. %,after 6 hours at least 30 wt. %, after 12 hours at least 50 wt. %, after18 hours at least 70 wt. %, and after 24 hours at least 80 wt. % of saidactive ingredient originally contained in the dosage form; and whereinthe release of said active ingredient is measured in accordance with theEuropean Pharmacopoeia with a paddle stirrer apparatus in buffer at a pHvalue of 6.8, a temperature of 37° C. and 75 rpm.
 36. A dosage form asclaimed in claim 34, wherein the release of said active ingredient fromsaid dosage form satisfies the relation:0.010 hour⁻¹ ≦C _(max) /AUC≦0.150 hour⁻¹., wherein C_(max) representsthe maximum measured plasma concentration of the active ingredient, andAUC represents the area under the plasma concentration/time curve.
 37. Adosage form as claimed in claim 34, wherein at an identical dose D,t_(1/2,z) is higher than in a comparison formulation without controlledrelease.
 38. A dosage form as claimed in claim 34, wherein t_(1/2,z)>5.7hours.
 39. A dosage form as claimed in claim 34, wherein said dosageform produces a mean residence time greater than 7.5 hours.
 40. A dosageform as claimed in claim 34, wherein said dosage form produces a halfvalue duration greater than 5.0 hours.
 41. A dosage form as claimed inclaim 34, wherein said dosage form contains an active ingredient dose D,and upon administration of said dosage form, the release of said activeingredient from said dosage form satisfies the relation:7.0 10⁻⁵ l⁻¹ ≦C _(max) /D≦1.05 10⁻³ l⁻¹, where C_(max) represents amaximum measured plasma concentration.
 42. A dosage form as claimed inclaim 34, wherein upon twice daily administration, said dosage formproduces a peak to trough fluctuation of less than 80%.
 43. A dosageform as claimed in claim 34, wherein said dosage form comprises apolymer matrix from which at least a portion of the total dose of saidactive ingredient contained in the dosage form is released in a delayedmanner.
 44. A dosage from as claimed in claim 34, wherein said dosageform comprises a film coating which releases at least a portion of thetotal dose of said active ingredient contained in the dosage form in adelayed manner.
 45. A dosage form as claimed in claim 34, wherein saiddosage form comprises a polymer matrix in which at least a portion ofsaid active ingredient is embedded, said polymer matrix being based on acellulose ether or cellulose ester which in an aqueous solution at aconcentration of 2.0 wt. % at 20° C. has a viscosity in the range from3,000 to 150,000 mPa·s.
 46. A dosage form as claimed in claim 45,wherein the cellulose ether or cellulose ester is selected from thegroup consisting of methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcelluloseand hydroxypropylmethylcellulose.
 47. A dosage form as clamed in claim45, wherein polymer matrix comprises from 5.0 to 85 wt.-% of the totalweight of the dosage form.
 48. A dosage form as claimed in claim 45,wherein the relative weight ratio of the polymer matrix to the activeingredient is in the range from 3:1 to 1:10.
 49. A dosage form asclaimed in claim 45, wherein the polymer matrix comprises from 15 to 35wt. % of a hydroxypropylmethylcellulose relative to the total weight ofthe dosage form; said hydroxypropylmethylcellulose having a viscosity inthe range from 50,000 to 130,000 mPa·s in an aqueous solution at aconcentration of 2.0 wt. % and at 20° C.
 50. A dosage form as claimed inclaim 45, wherein said dosage form contains a filler in an amount suchthat the relative weight ratio of the filler to the polymer matrix isless than 6:1.
 51. A dosage form as claimed in claim 50, wherein saidfiller is selected from the group consisting of: fillers soluble in anaqueous medium; non-swelling fillers insoluble in an aqueous medium, andswelling fillers insoluble in an aqueous medium.
 52. A dosage form asclaimed in claim 34, wherein the active ingredient is(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol or a pharmaceuticallyacceptable salt thereof.
 53. A dosage form as claimed in claim 34,wherein said dosage form comprises from 0.5 to 85 wt.-% of said activeingredient relative to the total weight of the dosage form.
 54. A dosageform as claimed in claim 34, wherein said dosage form produces an invivo peak plasma level of said active ingredient from 3 to 8 hours afteradministration.
 55. A dosage form as claimed in claim 34, wherein saiddosage form is formulated for once or twice daily administration.
 56. Adosage form as claimed in claim 34, wherein said dosage form isformulated for oral or rectal administration.
 57. A dosage form asclaimed in claim 34, wherein said dosage form is in tablet form.
 58. Apharmaceutical composition comprising:3-(2-dimethylaminomethylcyclohexyl)phenol or a pharmaceuticallyacceptable salt thereof, and a cellulose ether or cellulose ester whichin an aqueous solution at a concentration of 2.0 wt. % and at 20° C. hasa viscosity in the range from 3,000 to 150,000 mPa·s.
 59. A compositionas claimed in claim 58, wherein said cellulose ether or cellulose esteris selected from the group consisting of methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose and hydroxypropylmethylcellulose.
 60. A method oftreating pain in a subject, said method comprising administering to saidsubject an effective pain treating amount of3-(2-dimethylaminomethylcyclohexyl)phenol or a pharmaceuticallyacceptable salt thereof in a pharmaceutical dosage form as claimed inclaim 34, whereby the treatment is accompanied by a reduction inside-effect nausea or vomiting or both in comparison to treatment with3-(2-dimethylaminomethylcyclohexyl)phenol or a pharmaceuticallyacceptable salt thereof in a dosage form without controlled release. 61.A method as claimed in claim 60, wherein the pharmaceutical dosage formis administered orally.
 62. A method as claimed in claim 60, whereinsaid pain is acute pain or chronic pain.
 63. A method of treating painin a subject, said method comprising administering to said subject aneffective pain treating amount of3-(2-dimethylaminomethylcyclohexyl)phenol or a pharmaceuticallyacceptable salt thereof in a pharmaceutical dosage form as claimed inclaim 34, wherein said pharmaceutical dosage form reaches a peak plasmalevel of said active ingredient from 2 to 10 hours after administration.